Maternally expressed, paternally imprinted, embryonic non-coding RNA are expressed in osteosarcoma, Ewing sarcoma and spindle cell sarcoma

In a human embryo it takes 8 weeks after fertilisation for the skeleton to begin to form, one of the last organs to develop before becoming a foetus. Mesenchymal progenitors, derived from neural crest cells, differentiate into chondrocytes where the skeleton is generated as a mostly cartilage template. Other mesenchymal progenitors envelop the template, activate runt related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2) and differentiate into osteoblasts, where an osteoid matrix is secreted and subsequently mineralised to become bone.1 During development and up to late adolescence, cellular proliferation enabling skeletal growth is restricted to the metaphysis and epiphyseal line or “growth plate”. It is in the growth plate of long bones where most bone cancers develop, hence the predominantly childhood incidence of the cancer. Primitive mesenchymal cells undergo transformation to form a heterogeneous group of bone malignancies. The most common type of bone cancer in children is osteosarcoma, mostly initiated by tumour protein p53 (TP53) mutations. The second most common type of bone cancer in children is Ewing sarcoma, mostly initiated by a EWS RNA binding protein 1-Fli-1 proto-oncogene, ETS transcription factor (EWSR1-FLI1) fusion. There are an average of 160 and 55 new cases of osteosarcoma and Ewing sarcoma, respectively, every year in the UK. Five-year survival for both cancer types is 50% when diagnosed early. Five-year survival is 15% when lung metastases are present at diagnosis. Treatment progress for bone cancer is poor when compared to other cancers such as breast where there is a twenty-year survival of 70%. Bone cancer requires extensive and sometimes disabling multimodal treatment. Chemotherapy for osteosarcoma includes methotrexate, cisplatin and doxorubicin, which were developed in the 1940’s and 1970’s. Chemotherapy for Ewing sarcoma includes vincristine, ifosfamide and etoposide, which were developed in the 1960’s and 1980’s. If the tumour responds well to chemotherapy and radiotherapy, wide area resection or amputation is performed. New understanding of bone cancer biology leading to better diagnosis and better treatments is required

Climate change drives expansion of Antarctic ice-free habitat

Antarctic terrestrial biodiversity occurs almost exclusively in ice-free areas that cover less than 1% of the continent. Climate change will alter the extent and configuration of ice-free areas, yet the distribution and severity of these effects remain unclear. Here we quantify the impact of twenty-first century climate change on ice-free areas under two Intergovernmental Panel on Climate Change (IPCC) climate forcing scenarios using temperature-index melt modelling. Under the strongest forcing scenario, ice-free areas could expand by over 17,000 km2 by the end of the century, close to a 25% increase. Most of this expansion will occur in the Antarctic Peninsula, where a threefold increase in ice-free area could drastically change the availability and connectivity of biodiversity habitat. Isolated ice-free areas will coalesce, and while the effects on biodiversity are uncertain, we hypothesize that they could eventually lead to increasing regional-scale biotic homogenization, the extinction of less-competitive species and the spread of invasive species

Effective connectivity measured using optogenetically evoked hemodynamic signals exhibits topography distinct from resting state functional connectivity in the mouse

Brain connectomics has expanded from histological assessment of axonal projection connectivity (APC) to encompass resting state functional connectivity (RS-FC). RS-FC analyses are efficient for whole-brain mapping, but attempts to explain aspects of RS-FC (e.g., interhemispheric RS-FC) based on APC have been only partially successful. Neuroimaging with hemoglobin alone lacks specificity for determining how activity in a population of cells contributes to RS-FC. Wide-field mapping of optogenetically defined connectivity could provide insights into the brain\u27s structure-function relationship. We combined optogenetics with optical intrinsic signal imaging to create an efficient, optogenetic effective connectivity (Opto-EC) mapping assay. We examined EC patterns of excitatory neurons in awake, Thy1-ChR2 transgenic mice. These Thy1-based EC (Thy1-EC) patterns were evaluated against RS-FC over the cortex. Compared to RS-FC, Thy1-EC exhibited increased spatial specificity, reduced interhemispheric connectivity in regions with strong RS-FC, and appreciable connection strength asymmetry. Comparing the topography of Thy1-EC and RS-FC patterns to maps of APC revealed that Thy1-EC more closely resembled APC than did RS-FC. The more general method of Opto-EC mapping with hemoglobin can be determined for 100 sites in single animals in under an hour, and is amenable to other neuroimaging modalities. Opto-EC mapping represents a powerful strategy for examining evolving connectivity-related circuit plasticity

The impact on passenger car emissions associated with the promotion and demise of diesel fuel

The promotion and growth in the use of diesel fuel in passenger cars in the UK and Europe over the past two decades led to considerable adverse air quality impacts in urban areas and more widely. In this work, we construct a multi-decade analysis of passenger car emissions in the UK based on real driving emissions data. An important part of the study is the use of extensive vehicle emission remote sensing data covering multiple measurement locations, time periods, environmental conditions and consisting of over 600,000 measurements. These data are used to consider two scenarios: first, that diesel fuel use was not promoted in the early 2000s for climate mitigation reasons, and second, that there was not a dramatic decline in diesel fuel use following the Dieselgate scandal. The strong growth of diesel fuel use coincided with a time when diesel NOx emissions were high and, conversely, the strong decrease of diesel fuel use coincided with a time when diesel vehicle after-treatment systems for NOx control were effective. We estimate that the growth in diesel car use in the UK results in excess NOx emissions of 721 kt over a three decade period; equivalent to over 7 times total annual passenger car NOx emissions and greater than total UK NOx emissions of 681.8 kt in 2021 and with an associated damage cost of £5.875 billion. However, the sharp move away from diesel fuel post-Dieselgate only reduced NOx emissions by 41 kt owing to the effectiveness of modern diesel aftertreatment systems

The socio-technical organisation of community pharmacies as a factor in the Electronic Prescription Service Release Two implementation: a qualitative study

Background The introduction of a new method of transmitting prescriptions from general practices to community pharmacies in England (Electronic Prescription Service Release 2 (EPS2)) has generated debate on how it will change work practice. As EPS2 will be a key technical element in dispensing, we reviewed the literature to find that there were no studies on how social and technical elements come together to form work practice in community pharmacies. This means the debate has little point of reference. Our aim therefore was to study the ways social and technical elements of a community pharmacy are used to achieve dispensing through the development of a conceptual model on pharmacy work practice, and to consider how a core technical element such the EPS2 could change work practice. Method We used ethnographic methods inclusive of case-study observations and interviews to collect qualitative data from 15 community pharmacies that were in the process of adopting or were soon to adopt EPS2. We analysed the case studies thematically and used rigorous multi-dimensional and multi-disciplinary interpretive validation techniques to cross analyse findings. Results In practice, dispensing procedures were not designed to take into account variations in human and technical integration, and assumed that repetitive and collective use of socio-technical elements were at a constant. Variables such as availability of social and technical resources, and technical know-how of staff were not taken into account in formalised procedures. Yet community pharmacies were found to adapt their dispensing in relation to the balance of social and technical elements available, and how much of the social and technical elements they were willing to integrate into dispensing. While some integrated as few technical elements as possible, some depended entirely on technical artefacts. This pattern also applied to the social elements of dispensing. Through the conceptual model development process, we identified three approaches community pharmacies used to appropriate procedures in practice. These were ‘technically oriented’, ‘improvising’ or ‘socially oriented’. Conclusion We offer a model of different work approaches community pharmacies use to dispense, which suggests that when adopting a core technical element such as the EPS2 system of dispensing there could be variations in its successful adoption. Technically oriented pharmacies might find it easiest to integrate a similar artefact into work practice although needs EPS2 to synchronise effectively with existing technologies. Pharmacies adopting an improvising-approach have the potential to improve how they organise dispensing through EPS2 although they will need to improve how they apply their operating procedures. Socially oriented pharmacies will need to dramatically adapt their approach to dispensing since they usually rely on few technical tools

CoastColour Round Robin data sets: A database to evaluate the performance of algorithms for the retrieval of water quality parameters in coastal waters

The use of in situ measurements is essential in the validation and evaluation of the algorithms that provide coastal water quality data products from ocean colour satellite remote sensing. Over the past decade, various types of ocean colour algorithms have been developed to deal with the optical complexity of coastal waters. Yet there is a lack of a comprehensive intercomparison due to the availability of quality checked in situ databases. The CoastColour Round Robin (CCRR) project, funded by the European Space Agency (ESA), was designed to bring together three reference data sets using these to test algorithms and to assess their accuracy for retrieving water quality parameters. This paper provides a detailed description of these reference data sets, which include the Medium Resolution Imaging Spectrometer (MERIS) level 2 match-ups, in situ reflectance measurements, and synthetic data generated by a radiative transfer model (HydroLight). These data sets, representing mainly coastal waters, are available from doi:10.1594/PANGAEA.841950. The data sets mainly consist of 6484 marine reflectance (either multispectral or hyperspectral) associated with various geometrical (sensor viewing and solar angles) and sky conditions and water constituents: total suspended matter (TSM) and chlorophyll a (CHL) concentrations, and the absorption of coloured dissolved organic matter (CDOM). Inherent optical properties are also provided in the simulated data sets (5000 simulations) and from 3054 match-up locations. The distributions of reflectance at selected MERIS bands and band ratios, CHL and TSM as a function of reflectance, from the three data sets are compared. Match-up and in situ sites where deviations occur are identified. The distributions of the three reflectance data sets are also compared to the simulated and in situ reflectances used previously by the International Ocean Colour Coordinating Group (IOCCG, 2006) for algorithm testing, showing a clear extension of the CCRR data which covers more turbid waters

A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol

Background: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. Objective: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. Design: Observational prospective cohort study. Setting: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). Patients: Three hundred adults and 300 children planned to receive cisplatin therapy. Measurements: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. Methods: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. Limitations: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. Conclusions: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices

Field performance of switchgrass plants engineered for reduced recalcitrance

Switchgrass (Panicum virgatum L.) is a promising perennial bioenergy crop that achieves high yields with relatively low nutrient and energy inputs. Modification of cell wall composition for reduced recalcitrance can lower the costs of deconstructing biomass to fermentable sugars and other intermediates. We have engineered overexpression of OsAT10, encoding a rice BAHD acyltransferase and QsuB, encoding dehydroshikimate dehydratase from Corynebacterium glutamicum, to enhance saccharification efficiency in switchgrass. These engineering strategies demonstrated low lignin content, low ferulic acid esters, and increased saccharification yield during greenhouse studies in switchgrass and other plant species. In this work, transgenic switchgrass plants overexpressing either OsAT10 or QsuB were tested in the field in Davis, California, USA for three growing seasons. No significant differences in the content of lignin and cell wall-bound p-coumaric acid or ferulic acid were detected in transgenic OsAT10 lines compared with the untransformed Alamo control variety. However, the transgenic overexpressing QsuB lines had increased biomass yield and slightly increased biomass saccharification properties compared to the control plants. This work demonstrates good performance of engineered plants in the field, and also shows that the cell wall changes in the greenhouse were not replicated in the field, emphasizing the need to validate engineered plants under relevant field conditions

Identification of genetic effects underlying Type 2 Diabetes in South Asian and European populations

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n=16,677) and controls (n=33,856), followed by combined analyses with Europeans (neff=231,420). We identify 21 novel genetic loci for significant association with T2D (P=4.7x10-8 to 5.2x10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations